Competitive PCR was used to evaluate the expression of cytokine, granzyme B, and chemokine genes in lymph nodes of macaques recently infected with the simian immunodeficiency virus (SIV) pathogenic molecular clone SIVmac239 (n = 16), the nonpathogenic vaccine strain SIVmac239 D nef (n = 8), and the nonpathogenic molecular clone SIVmacA11 (n = 8). For both SIVmac239 and its nef-deleted derivative, strong expression was observed as early as 7 days postinfection for interleukin 1b(IL-1b, IL-6, tumor necrosis factor alpha, gamma interferon and IL-13. The levels of gene induction were equally intense for both viruses despite a lower viral load for SIVmac239 Dnef compared with that for SIVmac239. However, the nature of the cytokine network activation varied with the viral inocula. Primary infection with SIVmac129 was characterized by a higher level of IL-4, IL-10, MIL-1a, MIP-1b, MCP-1, and RANTES gene expression and a lower level of IL-12 and granzyme B gene expression compared with infection with SIVmac239Dnef. Thus, infection with nef-deleted SIV was associated with a preferential TH1 versus TH2 pattern of cytokine production. Infection with SIVmacA11 was characterized by a delayed immune response for all markers tested. The unique patterns of cytokine and chemokine gene expression in lymph nodes correlated nicely with the pathogenic potential of the SIV strains used as well as with differences in their ability to serve as protective vaccines.